Endocrine System

Question 1

Describe the structure and functions of the hypothalamus.

Answer 1

The hypothalamus regulates and oversees many functions within the endocrine system, and presents the interface between the endocrine and nervous systems via the pituitary gland (by receiving neuronal input, and supplying neuronal and endocrine output to the pituitary). It is located in the lower part of the diancephalon of the brain, superior to the pituitary gland, and connected to the pituitary stalk (AKA infundibulum).

Question 2

Describe the structure and functions of the anterior and posterior pituitary gland.

Answer 2

The pituitary gland is a ductless gland. The infundibulum carries hypophyseal-pituitary portal blood supply, and it sits in the pituitary fossa of the sphenoid bones. The pituitary gland can be sub-divided into the anterior (adenohypophysis) and posterior (neurohypophysis) glands.

The posterior pituitary consists of the pituitary stalk and pars nervosa, and carries the hypothalamo-hypophyseal (H-H) nerve tract. Hormones synthesised in the hypothalamus travel through the H-H tract via axoplasmic transport to the posterior pituitary, where they are stored in neurosecretory granules for excretion in response to action potentials. It also contains unmyelinated axons of neuro-secretory neurons (cell bodies comprised of paraventricular and supraoptic nuclei of the hypothalamus).

The anterior pituitary consists of 3 main regions - the pars distalis pars intermedia, and pars tuberalis. It is stimulated/inhibited by the hypothalamus hormones which influence the release of pituitary hormones. Hypothalamic hormones travel to the anterior pituitary via the hypophyseal-pituitary portal blood supply. Anterior pituitary hormones are short-lived polypeptides which bind to surface receptors (growth hormones, thyroid-stimulating hormone, etc). Cell types in the anterior pituitary include somatotrophs (produce HGH), gonadocytes (produce LH/FSH), thyrotrophs (produce TSH), and corticotrophs (produce ACTH).

Question 3

Describe the structure and functions of the thyroid gland.

Answer 3

The thyroid gland is a vascularised, large, shield-shaped gland with two lobes. It lies ventro-lateral to the trachea, just inferior to the thyroid cartilage. The two lobes are connected by a central isthmus across the anterior aspect of the trachea.

There are two thyroid hormones - T3 (triiodothyronine) and T4 (thyroxine). The thyroid gland contains follicles (spheres of simple cuboidal epithelium, where T3 and T4 are stored and released in response to TSH). Iodine is required for thyroid hormone synthesis - comes from diet (seafood, dairy, kelp, etc). It also contains parafollicular/C cells which produce calcitonin, involved in calcium homeostasis. On the posterior aspect of the thyroid lobes, they each have two smaller glands called parathyroid glands (2x inferior, 2x superior). These have two major cell types:

1) Parathyroid (chief) cells - produce parathyroid hormones, involved in calcium homeostasis.
2) Oxyphil cells - have an unknown function.

Question 4

Describe the structure and functions of the pancreas.

Answer 4

The pancreas is a leaf-shaped, retro-peritoneal (behind sheets of peritoneum) organ which has both exocrine and endocrine function.
The endocrine function is the regulation of blood sugar homeostasis. The functional units are Islets of Langerhans, comprised of alpha cells which produce glucagon, beta cells which produce insulin, and gamma cells which produce somatostatin. There are around 1 million islets within the pancreas, distributed along the exocrine ducts.

Question 5

Describe the structure and functions of the adrenal glands.

Answer 5

Adrenal glands are pyramidal shaped glands which sit on top of the kidneys. There are three main layers to the adrenal glands - an outer capsule, a cortex, and an inner medulla. The medulla produces adrenaline and noradrenaline. The outer cortex secretes steroid hormones and androgens (and is further divided into 3 zones - the inner cortex (zone reticularis) which secretes androgen, the intermediate cortex (zone fasciculata) which secretes cortisol, and the outer cortex (zone glomerulosa) which secretes aldosterone).

Question 6

Explain the four main methods of cell signalling.

Answer 6

1) Endocrine signalling: this involves the production and secretion of a hormone from an endocrine gland into the bloodstream. The hormone reaches target tissues and attached to a receptor to stimulate a response. This is about one cell acting on a remote cell (example is insulin release from the pancreas acts upon distant adipose tissue to initiate lipogenesis)
2) Paracrine signalling: secretory cells are situated directly adjacent to the target cell. This is a local signalling strategy (example is somatostatin release by pancreatic cells acting locally – also, neurotransmission is a kind of paracrine signalling)
3) Autocrine signalling: signalling molecules acts upon the same cell which released it (example is neurotransmitter pre-synaptic inhibitors – SSRIs, another example is growth factors)
4) Plasma membrane-attached proteins: signalling molecules are presented on a cell and target cell binds its receptors to the signal molecules (example, signalling by T cells in the immune system)

Question 7

Describe the process of signal transduction by G-protein-coupled receptors.

Answer 7

G-proteins are trimeric (composed of 3 subunits - alpha, beta, gamma) signal transducers that bind to either GTP or GDP.

When an agonist binds to the receptor, it changes conformation, which subsequently increases the intracellular domain of the receptor affinity for the alpha subunit of the G protein. The Alpha subunit dissociates from the other two subunits and attached to the receptor, and then its affinity for GDP reduces, and the GDP dissociates in favour of a GTP molecule. The binding of GTP changes the conformation of the alpha subunit, resulting in it dissociating from the receptor (and subsequently, the agonist dissociates from the receptor), and the now active alpha subunit acts upon a transmembrane target protein (meanwhile, the beta-gamma subunit is actively acting on a second transmembrane target protein). GTPase built into the alpha subunit hydrolyses GTP to GDP + Pi and restores the whole thing to its resting state.

Question 8

Describe the process of signal transduction by ligand-gated ion channels.

Answer 8

Ligand-gated ion channels (ionotropic receptors) open ion channels in response to the attachment of an agonist signalling molecule. This results in the influex of ions (positive ions = depolarisation, negative = hyperpolarisation (inhibitory)).

Question 9

Describe the process of signal transduction by tyrosine-kinase-linked receptors.

Answer 9

Tyrosine-kinase-coupled receptors are comprised of an extracellular receptor and intracellular tyrosine kinase domain which are separated by a transmembrane alpha-helix. When the receptor binds, a conformational change results in dimerisation (two subunits associate). Tyosine kinase domain subunits autophorphorylate (phosphorylate themselves), changing their conformation. This allows downstream SH2 domain proteins to bind to the phosphotyrosine residues, subsequently activating a monomeric G-protein (one subunit), which then initiates its own kinase cascade.

Question 10

Describe the process of signal transduction by nuclear receptors.

Answer 10

Nuclear receptors involve an agonist attaching to a receptors within the nucleus which alters gene transcription (transcription factors such as sex hormones glucocorticoids, corticosteroids, etc) - this is not technically signal transduction.

Question 11

Describe the biosynthesis, storage, release, transport, and action of polypeptide hormones.

Answer 11

Proteins and polypeptides are the most common type of hormones. They are hydrophilic, and are produced in glands all over the body. They are often synthesised as pre-pro hormones which require further modification in order to be activated. They are stored in cell vesicles until they are triggered for release, and they are water-soluble, so circulate in the blood (dissolved in plasma). They act via cell surface membranes (second messenger system).

Examples include insulin, HGH, etc.

Question 12

Describe the biosynthesis, release, transport, and action of steroid hormones.

Answer 12

Steroid hormones are hydrophobic, and are produced in the gonads and placenta, or adrenal cortex. They are synthesised in a series of reaction pathways, all derived from cholesterol. Not stored prior to secretion, but are released immediately upon synthesis, and circulate bound to plasma proteins in the blood as they are insoluble in water. Albumin can typically carry any steroid hormones, but each hormone often has a greater affinity to a specific carrier. They act upon intracellular receptors (can easy pass through membranes as they are lipid-soluble), either within the cytosol or the nucleus itself – ultimately mediating gene transcription.

Examples include oestrogen, testosterone, cortisol, aldosterone, etc.

Question 13

Describe the biosynthesis, storage, release, transport, and action of amino acid derivatives.

Answer 13

Amino acid derivatives are produced in the thyroid and adrenal medullae, and can be hydrophobic or hydrophilic. They are synthesised from amino acids and stored before released (method of storage varies). They ave a range of methods of circulating – for example, adrenaline is water soluble, 50% of it is dissolved in circulation, and the other half is bound to albumin to be transported. Some amino acid derivatives work via cell surface receptors, others act within the cell (depends on their solubility). Only free circulating hormones are active (i.e. if 50% is bound to proteins, it does not contribute to the active amount).

Examples include thyroxine and adrenaline (both derivatives of tyrosine).

Question 14

Using an example, explain negative feedback control of hormone secretion.

Answer 14

Negative feedback loops allow for changes in tightly controlled conditions to be mediated such that they constantly tend towards the optimum condition. When a stimulus disrupts the controlled condition, receptors detect this and send afferent signals to a control centre. This control centre receives various inputs and provides an efferent output on effectors which alter the body’s physiology in order to maintain homeostasis.

For example, a fall in blood calcium (stimulus) disrupts blood calcium concentration (controlled condition). Calcium receptors in the parathyroid cell membranes (receptors) detect this, and send signals to the parathyroid gland (control centre). The parathyroid gland then produces parathyroid hormones, which uses several downstream pathways (increased calcium uptake from the gut by increased action of vitamin D, increased calcium reabsorption in the kidneys, increased calcium release from bones, etc) to restore normal blood calcium levels.

Multiple feedback loops are usually all working simultaneously to allow for fine-tuning. There are different lengths of feedback loop which all operate together:

1) Long-loop feedback - target gland hormones feed back to the control centre to reduce the secretion of more hormone.
2) Short-loop feedback - intermediate glands feed back to the control centre (e.g. pituitary gland feeds back to hypothalamus), this is important if the target gland is not functioning properly.
3) Ultra-short-loop feedback - hormones feed back within the control centre itself (paracrine and autocrine efects inhibit its own production).

Question 15

Using an example, explain positive feedback control of hormone secretion.

Answer 15

Positive feedback loops are responsible for pushing specific events to completion. In positive feedback, a stimulus effects the controlled condition, and receptors detect this stimulus and feed back the information to a control centre (same as negative). However, rather than mediating the effects of the stimulus to restore homeostasis, the control centre sends signals to efferent effectors to further exacerbate the condition.

An example of positive feedback in the endocrine system is labour in childbirth (must be continued to completion in order for the health of the mother and baby to be ensured). In this example, contractions in the uterus push the baby’s head against the cervix (stimulus), which affects cervical dilation (controlled condition). Stretch sensitive nerve cells in the cervix detect this (receptors), and send signals to a control centre in the brain, which sends efferent signals to muscles in the uterus wall (via oxytocin), increasing dilation of the cervix, pushing the baby further, causing more stretch against the cervix, and the cycle continues until the event has completed.

Question 16

Using an example, explain feed-forward control of hormone secretion.

Answer 16

Feed-forward control is an adapted response due to the anticipation of a stimulus which is not yet acting on the body. For example, when an individual knows they are about to begin exercise, they will anticipate this, and their heart rate and ventilation will increase before the exercise begins.

Another example of this is lactation (uses both feed-forward and positive feedback control). Here, when a breastfeeding mother hears the baby crying for milk, oxytocin is released from the posterior pituitary in response to the anticipation (before suckling begins). Then, when suckling begins, further oxytocin (+ prolactin) is released. Oxytocin stimulates its own production and release, and the mother may begin to feel thirsty (another feed-forward mechanism).

Question 17

Outline the process by which the renin-angiotensin-aldosterone system homeostatically controls water balance.

Answer 17

Aldosterone regulates sodium excretion and reabsorption, and is also responsible for mediating water balance within the body. Juxtaglomerular kidney apparatus activates the renin-angiotensin system, which subsequently stimulates the production and release of aldosterone from the adrenal cortex upon decreased blood volume or pressure (can also be stimulated by adrenocorticotropic hormone, or increased potassium concentration).
Once it reaches the target tissues, aldosterone diffuses through the membrane and acts via an intracellular receptor within the cytoplasm of renal tubular cells. The aldosterone-receptor complex then diffuses to the nucleus, where it promotes the production of mRNA for Na+/K+ ATPase and epithelial sodium channels. This enables the reabsorption of sodium through the kidneys, subsequently increasing water reabsorption, restoring normal blood volume and pressure (increased circulating blood plasma volume).

Question 18

Outline the process by which the hypothalamic-pituitary axis homeostatically controls water balance.

Answer 18

Antidiuretic hormone (ADH, AKA vasopressin) is a peptide hormone synthesised in the hypothalamus, and stored in secretory granules within the posterior pituitary. It is synthesised by ribosomes on the RER as a pre-prohormone, then the signal peptide is cleaved as it is transported to the ER (making it a prohormone), which is then packaged in a secretory granule at the ER/golgi, and proteolytically cleaved upon secretion to activate it (exact same mechanism as insulin). It acts via G-protein-coupled receptors either on arterioles, causing vasoconstriction (increasing blood pressure – V1 receptors), or on V2 receptors in the basolateral membrane of the collecting tubule cells of the kidney

Once it binds, V2 receptors use the cyclic AMP secondary messenger cascade to recruit aquaporins from storage vesicles within the cell to the surface, facilitating the diffusion of water. This allows for increased water reabsorption in the kidney tubules, which results in increased circulating volume, and more concentrated urine (decreased blood plasma osmolarity).

Question 19

Describe the production, secretion, and mode of action of thyroid hormones.

Answer 19

The main two thyroid hormones are triiodothyronine (T3) and tetraiodothyronine (AKA thyroxine, T4). These are both derivatives of tyrosine (non-essential amino acid) with iodines added.

Thyroglobulin is the matrix for thyroid hormone synthesis, and the form in which they are stored in the gland (forms gel-like substance called colloid - necessary because they are lipid-soluble, so could diffuse through a membrane). Thyroglobulin is synthesised within follicular cells, on ribosomes, before being glycosylated in the ER, and translocated to the golgi to be packaged and exocytosed into the follicular lumen at the apical surface. Each thyroglobulin contains about 70 tyrosines.

Iodine in the diet is reduced to iodide, which travels via the blood (bound to albumin) to the thyroid gland. It is then actively transported into the thyroid follicular cells via socium/iodine symporters on their basolateral aspect (1x iodide for 2x sodium). At the apical membrane, a transporter called Pendrin exchanges iodide for chloride, allowing the iodide to move into the follicular lumen. An enzyme called thyroid peroxidase then oxidises iodide back to iodine, and catalyses the binding of iodine to the tyrosine residues of thyroglobulin - either one or two iodine atoms bind at first (creating either monoiodothyronine or diiiodothronine). Then a mino joins with a di to make a try (T3) or two di’s join to make a tetra (T4).

When stimulated to release, thyroglobulin is endocytosed into follicle cells, which combine with lysosomes, digesting thyroglobulin and releasing T3&4 at the basal side of the cell, where specific transporters move them into the bloodstream. Most thyroid hormones don’t circulate freely, but are bound to thyroid-binding globulin, or sometimes transthyretin or albumin.

T3&4 hormones affect nearly every cell in the body. They enter via active transporters. T4 is essentially a prohormone for T3, as it is converted to T3 within the cytosol of target cells. T3 binds to receptors already attached to promoter regions of nuclear DNA where is promotes or inhibits transcription (usually promotes).

Question 20

Outline the production and secretion of cortisol.

Answer 20

Production of cortisol is mediated by the hypothalamic-pituitary-adrenal axis (HPA). Various stressors such as exercise, fear, and inflammation stimulate the release of corticotropic releasing hormone (CRH) from the hypothalamus. CRH then stimulates the production of adrenocorticotropic hormone (ACTH) from the anterior pituitary (peptide hormone which acts via G-protein-coupled receptors which activates steroidogenic acute regulatory protein (STAR protein) which moves cholesterol from outer to inner mitochondrial membrane – the rate limiting step in steroid hormone production) – this pathway of ACTH takes minutes. ACTH also affects gene expression in various enzymes responsible for cortisol synthesis, this pathway takes hours. The cortisol produced has an inhibitory feedback effect on the hypothalamus to maintain homeostasis. ACTH also stimulates cell growth and survival of cells within the adrenal gland.

Cortisol is transporter in the blood, mainly bound to corticosteroid-binding globulin (CBG), but some is also bound to albumin, and about 3-4% is transported freely in the blood. Most cells in the body have cortisol receptors (glucocorticoid receptor is found in the cytoplasm of most cells). The cortisol binds to the receptor, and the complex translocates into the nucleus where it binds to hormone response elements of cortisol-regulated genes (either induces or inhibits gene expression, depending on the gene). Cortisol secretion comes in waves and varies in a 24-hour cycle. There are, on average, 10 secretory bursts throughout the day, with the lowest points in the evening and shortly after falling asleep. The highest levels are early in the morning (may explain increased rates of heart attack in the morning).

Question 21

Describe some of the downstream effects of thyroid hormones.

Answer 21

Actions of thyroid hormone can be divided into two categories: metabolism and growth/development. They result in a general increase in energy metabolism, stimulate protein synthesis, Na/K ATPase activity, and the activity of mitochondria (all lead to increase in oxygen consumption and heat production – therefore the metabolic rate). On the cardiovascular system, thyroid hormones increase cardiac output, on the lungs, ventilation, and on the GI tract, secretions and motility. They also have effects on other endocrine glands increase secretions, as well as peripheral tissue hormone requirements. In growth and development, they are responsible for skeletal and nervous development.

Question 22

Explain the role of cortisol in the stress response.

Answer 22

The main functions of cortisol are to maintain blood glucose levels are protect the body from overactive inflammatory responses. It also affects foetal development. Most effects of cortisol are permissive (meaning it does not directly cause the effect). Cortisol stimulates gluconeogenesis, reduces uptake of glucose by skeletal muscle and adipose tissue, also increases lipolysis and proteolysis (catabolic hormone) – opposes the action of insulin. It increases adrenoreceptor expression in the cardiovascular system, and so supports the cardiovascular response to adrenalin and noradrenalin. It inhibits prostaglandin synthesis (immunosuppressant and anti-inflammatory). It increases renal excretion of calcium, also inhibits reproductive function and has effects on memory and learning.

When confronted with a stimulus such as extreme hot or cold, fear, etc, the sympathetic nervous system initiates a response via adrenaline and noradrenaline. Cortisol gives a “counter-shock” response, preventing damage caused by the sympathetic response, and ensures there is energy liberated for the fight or flight response, and also inhibits non-essential function (suppresses digestive and reproductive systems, as well as growth processes).

Perceived threats in the modern world can result in chronic stress. The general adaptation syndrome is a theory describing 3 stages to chronic stress. The first phase is the alarm phase (initiation of the fight or flight response mediated by the sympathetic nervous system), then the resistance phase (involves the body adapting to cope with the continued stress – continues to secrete cortisol), and finally, the exhaustion phase (reserves are depleted). Prolonged exposure to high levels of cortisol can lead to hypertension, hyperglycaemia, obesity, increased susceptibility to infections, immune suppression, inhibition of reproductive function, impaired memory, etc.